Healthy Volunteers
Conditions
Keywords
GnRH deficiency, GnRH antagonist, Letrozole, GnRH, FSH, LH, Inhibins
Brief summary
This research study involves the use of the drugs Letrozole, GnRH, and NAL-GLU GnRH antagonist. Letrozole is a drug that is approved by the U.S. Food and Drug Administration (FDA) for use in breast cancer treatment that has been found to block the formation of estrogen. The NAL-GLU GnRH antagonist is a drug that temporarily blocks the action of GnRH. GnRH is a hormone that the body makes that stimulates other hormones that then control the function of the ovary. The purpose is to study the effects of the administration of letrozole in women with GnRH deficiency at the same time that they receive gonadotropin-releasing hormone (GnRH). In addition, administration of letrozole and NAL-GLU GnRH antagonist in healthy women with normal menstrual cycles will be done to evaluate the role of estrogen in the control of the hormone FSH, or Follicle Stimulating Hormone, in the female reproductive cycle. A better understanding of FSH control may help in the development of new treatments for women with difficulty conceiving.
Detailed description
The negative feedback control of FSH is crucial for the precise regulation of follicular development in the female. An important component of this feedback is exerted by estrogen. Letrozole will be used to block aromatase and therefore estradiol production in normal and GnRH deficient females. These studies will dissect the relative roles of estradiol and inhibin on FSH secretion at the pituitary and hypothalamus. The aromatase inhibitors block aromatization of androgens to estrogens, allowing us to examine the relative contribution of estradiol and the inhibins to FSH regulation. The use of a submaximal dose of a GnRH antagonist will allow us to estimate the overall amount of GnRH secreted (hypothalamic contribution) with and without aromatase inhibition. A more thorough understanding of estrogen and inhibin feedback on FSH will improve our understanding of the failure of follicle development in subsets of patients with infertility, such as polycystic ovary syndrome, in which FSH levels are normal but follicles fail to develop. Study of FSH control will also help us understand the failure of negative feedback on FSH, which can result in multiple follicular development and multiple gestation and its associated costs and risks. Thus, these studies may afford new therapeutic options for conception in infertile patients while simultaneously providing new methods to avoid the risks of multiple gestations.
Interventions
DRUGLetrozole
Letrozole 20 mg orally one time
5 mcg/kg of the NAL-GLU GnRH antagonist subcutaneously
Sponsors
National Institutes of Health (NIH)
Massachusetts General Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Intervention model description
This is a physiologic study designed to investigate the relative roles of estradiol and inhibin A or inhibin B in the control of FSH secretion during normal menstrual cycles using an aromatase inhibitor. Subjects serve as their own control with no intervention in cycle 1 and letrozole administration in cycle 2. Subjects are studied in the early follicular phase or the late follicular phase.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
Healthy Normal Subjects will meet the following criteria: * 18 to 35 years of age * good general health * on no medications including any hormonal drug products for at least 3 months before the study * regular menstrual cycles every 25-35 days with ovulation documented by a luteal phase progesterone \> 3 ng/ml * no evidence of androgen excess * normal TSH, prolactin and hemoglobin * use of double-barrier contraception, permanent sterilization or abstinence during the cycle of study. * Negative pregnancy test (serum) at the beginning of each cycle of study * Normal Liver Function Test
Exclusion criteria
* History of liver and/or kidney disease * Substance or alcohol abuse * Hormone dependent neoplasia including breast cancer * Women who are trying to become pregnant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| FSH Level | EFP: average of menstrual cycle day 6 in the EFP; LFP: average of 2 days after follicle size of 16 mm | Difference in FSH peak following letrozole administration compared with control cycle |
Countries
United States
Participant flow
Pre-assignment details
Four subjects did not meet inclusion criteria (2 had increased prolactin, 2 had abnormal cycles) and were excluded after screening and before assignment to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Aromatase Inhibitor EFP Letrozole administration (20 mg) on day 2-4 (EFP; early follicular phase) of cycle 2 and
Nal-Glu GnRH antagonist used to estimate the overall amount of GnRH secreted.
Letrozole: Letrozole 20 mg orally one time
NAL-GLU GnRH antagonist: 5 mcg/kg of the NAL-GLU GnRH antagonist subcutaneously | 6 |
| Aromatase Inhibitor LFP Letrozole administration (20 mg daily x 2) at follicle size of \> 16 mm (LFP; late follicular phase) in cycle 2.
Nal-Glu GnRH antagonist used to estimate the overall amount of GnRH secreted.
Letrozole: Letrozole 20 mg orally one time
NAL-GLU GnRH antagonist: 5 mcg/kg of the NAL-GLU GnRH antagonist subcutaneously | 9 |
| Total | 15 |
Baseline characteristics
| Characteristic | Aromatase Inhibitor EFP | Total | Aromatase Inhibitor LFP |
|---|---|---|---|
| Age, Continuous | 27.2 years STANDARD_DEVIATION 5 | 27.9 years STANDARD_DEVIATION 4.4 | 28.5 years STANDARD_DEVIATION 4.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 13 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 12 Participants | 8 Participants |
| Region of Enrollment United States | 6 participants | 15 participants | 9 participants |
| Sex: Female, Male Female | 6 Participants | 15 Participants | 9 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 9 |
| other Total, other adverse events | 0 / 6 | 0 / 9 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 |
Outcome results
Primary
FSH Level
Difference in FSH peak following letrozole administration compared with control cycle
Time frame: EFP: average of menstrual cycle day 6 in the EFP; LFP: average of 2 days after follicle size of 16 mm
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aromatase Inhibitor EFP | FSH Level | 7.25 IU/L | Standard Error 2.42 |
| Aromatase Inhibitor LFP | FSH Level | 8.71 IU/L | Standard Error 1.58 |